Field testing of user-friendly perennial malaria chemoprevention packaging in Benin, Côte d'Ivoire and Mozambique.

BACKGROUND: Perennial malaria chemoprevention (PMC) aims to protect children at risk from severe malaria by the administration of anti-malarial drugs to children of defined ages throughout the year. Sulfadoxine-pyrimethamine (SP) has been widely used for chemoprevention in Africa and a child-friendly dispersible tablet formulation has recently become available. METHODS: This qualitative non-interventional observational study was conducted in Benin, Côte d'Ivoire, and Mozambique between February and June 2022. Prototype blister packs, dispensing boxes and job aids designed to support dispersible SP deployment for PMC were evaluated using focus group discussions (FGD) and semi-structured in-depth individual interviews (IDI) with health authorities, health personnel, community health workers (CHWs) and caregivers. The aim was to evaluate knowledge and perceptions of malaria and chemoprevention, test understanding of the tools and identify gaps in understanding, satisfaction, user-friendliness and acceptability, and assess the potential role of CHWs in PMC implementation. Interviews were transcribed and imported to ATLAS.ti for encoding and categorization. Thematic content analysis used deductive and inductive coding with cross-referencing of findings between countries and participants to enrich data interpretation. Continuous comparison across the IDI and FGD permitted iterative, collaborative development of materials. RESULTS: Overall, 106 participants completed IDIs and 70 contributed to FGDs. Malaria was widely recognised as the most common disease affecting children, and PMC was viewed as a positive intervention to support child health. The role of CHWs was perceived differently by the target groups, with caregivers appreciating their trusted status in the community, whereas health authorities preferred clinic-based deployment of PMC by health professionals. Empirical testing of the prototype blister packs, dispensing boxes and job aids highlighted the context-specific expectations of respondents, such as familiar situations and equipment, and identified areas of confusion or low acceptance. A key finding was the need for a clear product identity reflecting malaria. CONCLUSION: Simple modifications profoundly affected the perception of PMC and influenced acceptability. Iterative quantitative investigation resulted in PMC-specific materials suited to the local context and socio-cultural norms of the target population with the aim of increasing access to chemoprevention in children most at risk of severe malaria.

Evidence on sulfadoxine-pyrimethamine resistance molecular markers from India: interpret with caution.

BACKGROUND: Sulfadoxine-pyrimethamine (SP), as a partner to artesunate as ACT is the treatment of choice for uncomplicated P. falciparum infections in the majority of India and SP-resistance has a potential to lead to ACT failure. In the lack of robust surveillance of therapeutic efficacy of SP, validate molecular markers of SP-resistance offer a hint of failing SP. However, studies reporting these validated markers often suffer from certain pitfalls that warrant a careful interpretation. MAIN BODY: Critical analyses of the results and their reported interpretations from a recent study and other studies conducted on the WHO-validated molecular markers of SP-resistance in India were analysed and the main problems with studying and reporting of these markers are presented here. It was noted that almost all studies analysed flawed either on the usage, estimation and/or interpretation of the standardized classification of the studies SP mutations. These flaws not only impart spatiotemporal incomparability of the published data but also have the potential of being misunderstood and wrongly translated. CONCLUSION: Based on this universal problem in studying, reporting and interpreting the data from the studies on molecular markers of SP-resistance, it is stressed that the future studies should be conducted with utmost caution so that robust evidence may be generated and correctly translated to policy.

A quasi-experimental study to estimate effectiveness of seasonal malaria chemoprevention in Aweil South County in Northern Bahr El Ghazal, South Sudan.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is an effective intervention to prevent malaria in children in locations where the burden of malaria is high and transmission is seasonal. There is growing evidence suggesting that SMC with sulfadoxine-pyrimethamine and amodiaquine can retain its high level of effectiveness in East and Southern Africa despite resistance concerns. This study aims to generate evidence on the effectiveness of SMC when delivered under programmatic conditions in an area with an unknown anti-malarial drug resistance profile in the Northern Bahr el-Ghazal region of South Sudan. METHODS: A non-randomized quasi experimental study was conducted to compare an intervention county with a control county. Five monthly SMC cycles were delivered between July and November 2022, targeting about 19,000 children 3-59 months old. Data were obtained from repeated cross-sectional household surveys of caregivers of children aged 3-59 months using cluster sampling. Wave 1 survey took place in both counties before SMC implementation; Waves 2 and 3 took place after the second and fourth monthly SMC cycles. Difference-in-differences analyses were performed by fitting logistic regression models with interactions between county and wave. RESULTS: A total of 2760 children were sampled in the study across the three survey waves in both study counties. Children in the intervention arm had 70% lower odds of caregiver-reported fever relative to those in the control arm during the one-month period prior to Wave 2 (OR: 0.30, 95% CI 0.12-0.70, p = 0.003), and 37% lower odds in Wave 3 (OR: 0.63, 95% CI 0.22-1.59, p = 0.306) after controlling for baseline difference between counties in Wave 1. Odds of caregiver-reported RDT-confirmed malaria were 82% lower in the previous 1-month period prior to Wave 2 (OR: 0.18, 95% CI 0.07-0.49, p = 0.001) and Wave 3 (OR: 0.18, 95% CI 0.06-0.54, p = 0.003). CONCLUSION: These results show high effectiveness of SMC using SPAQ in terms of reducing malaria disease during the high transmission season in children 3-59 month. Despite the promising results, additional evidence and insights from chemoprevention efficacy cohort studies, and analyses of relevant resistance markers, are required to assess the suitability of SMC for this specific context.

Implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda: stakeholder engagement meeting report.

A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya, on 27 September 2023. Representatives from the respective National Malaria Control Programmes, the World Health Organization (WHO) Geneva, Africa Regional and Kenya offices, research partners, non-governmental organizations, and the Medicines for Malaria Venture participated. PDMC was recommended by the WHO in June 2022 and involves provision of a full anti-malarial treatment course at regular intervals during the post-discharge period in children hospitalized with severe anaemia in areas of moderate-to-high malaria transmission. The WHO recommendation followed evidence from a meta-analysis of three clinical trials and from acceptability, delivery, cost-effectiveness, and modelling studies. The trials were conducted in The Gambia using monthly sulfadoxine-pyrimethamine during the transmission season, in Malawi using monthly artemether-lumefantrine, and in Kenya and Uganda using monthly dihydroartemisinin-piperaquine, showing a significant reduction in all-cause mortality by 77% (95% CI 30-98) and a 55% (95% CI 44-64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. The objectives of the meeting were for the participating countries to share country contexts, plans and experiences regarding the adoption and implementation of PDMC and to explore potential delivery platforms in each setting. The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries. Meeting highlights included country consensus on use of dihydroartemisinin-piperaquine for PDMC and expansion of the target group to "severe anaemia or severe malaria", in addition to identifying country-specific options for PDMC delivery for evaluation in implementation research. Further exploration is needed on whether the age group should be extended to school-age children.

Seasonal Malaria Chemoprevention Drug Levels and Drug Resistance Markers in Children With or Without Malaria in Burkina Faso: A Case-Control Study.

BACKGROUND: Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children 3-59 months of age in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance. Using a case-control design, we determined associations between SMC drug levels, drug resistance markers, and presentation with malaria. METHODS: We enrolled 310 children presenting at health facilities in Bobo-Dioulasso. Cases were SMC-eligible children 6-59 months of age diagnosed with malaria. Two controls were enrolled per case: SMC-eligible children without malaria; and older (5-10 years old), SMC-ineligible children with malaria. We measured SP-AQ drug levels among SMC-eligible children and SP-AQ resistance markers among parasitemic children. Conditional logistic regression was used to compute odds ratios (ORs) comparing drug levels between cases and controls. RESULTS: Compared to SMC-eligible controls, children with malaria were less likely to have any detectable SP or AQ (OR, 0.33 [95% confidence interval, .16-.67]; P = .002) and have lower drug levels (P < .05). Prevalences of mutations mediating high-level SP resistance were rare (0%-1%) and similar between cases and SMC-ineligible controls (P > .05). CONCLUSIONS: Incident malaria among SMC-eligible children was likely due to suboptimal levels of SP-AQ, resulting from missed cycles rather than increased antimalarial resistance to SP-AQ.

The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.

Revisiting the Evidence Base for Modern-Day Practice of the Treatment of Toxoplasmic Encephalitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Toxoplasmic encephalitis (TE) is an opportunistic infection of people with human immunodeficiency virus (HIV) or other causes of immunosuppression. Guideline-recommended treatments for TE are pyrimethamine and sulfadiazine (P-S) or pyrimethamine and clindamycin (P-C); however, a substantial price increase has limited access to pyrimethamine. Consequently, some centers have transitioned to trimethoprim-sulfamethoxazole (TMP-SMX), an inexpensive alternative treatment. We aimed to review the evidence on the efficacy and safety of pyrimethamine-containing therapies vs TMP-SMX. METHODS: We searched for and included randomized controlled trials (RCTs) and observational studies of TE treatments, regardless of HIV status. Data for each therapy were pooled by meta-analysis to assess the proportions of patients who experienced clinical and radiologic responses to treatment, all-cause mortality, and discontinuation due to toxicity. Sensitivity analyses limited to RCTs directly compared therapies. RESULTS: We identified 6 RCTs/dose-escalation studies and 26 single-arm/observational studies. Identified studies included only persons with HIV, and most predated modern antiretroviral treatment. Pooled proportions of clinical and radiologic response and mortality were not significantly different between TMP-SMX and pyrimethamine-containing regimens (P > .05). Treatment discontinuation due to toxicity was significantly lower in TMP-SMX (7.3%; 95% confidence interval [CI], 4.7-11.4; I2 = 0.0%) vs P-S (30.5%; 95% CI, 27.1-34.2; I2 = 0.0%; P < .01) or P-C (13.7%; 95% CI, 9.8-18.8; I2 = 32.0%; P = .031). These results were consistent in analyses restricted to RCT data. CONCLUSIONS: TMP-SMX appears to be as effective and safer than pyrimethamine-containing regimens for TE. These findings support modern RCTs comparing TMP-SMX to pyrimethamine-based therapies and a revisiting of the guidelines.

Geographical emergence of sulfadoxine-pyrimethamine drug resistance-associated P. falciparum and P. malariae alleles in co-existing Anopheles mosquito and asymptomatic human populations across Cameroon.

Malaria molecular surveillance remains critical in detecting and tracking emerging parasite resistance to anti-malarial drugs. The current study employed molecular techniques to determine Plasmodium species prevalence and characterize the genetic diversity of Plasmodium falciparum and Plasmodium malariae molecular markers of sulfadoxine-pyrimethamine resistance in humans and wild Anopheles mosquito populations in Cameroon. Anopheles mosquito collections and parasitological survey were conducted in villages to determine Plasmodium species infection, and genomic phenotyping of anti-folate resistance was accomplished by sequencing the dihydrofolate-reductase (dhfr) and dihydropteroate-synthase (dhps) genes of naturally circulating P. falciparum and P. malariae isolates. The malaria prevalence in Elende was 73.5% with the 5-15 years age group harboring significant P. falciparum (27%) and P. falciparum + P. malariae (19%) infections. The polymorphism breadth of the pyrimethamine-associated Pfdhfr marker revealed a near fixation (94%) of the triple-mutant -A16I51R59N108I164. The Pfdhps backbone mediating sulfadoxine resistance reveals a high frequency of the V431A436G437K540A581A613 alleles (20.8%). Similarly, the Pmdhfr N50K55L57R58S59S114F168I170 haplotype (78.4%) was predominantly detected in the asexual blood stage. In contrast, the Pmdhps- S436A437occured at 37.2% frequency. The combined quadruple N50K55L57R58S59S114F168I170_ S436G437K540A581A613 (31.9%) was the major circulating haplotype with similar frequency in humans and mosquitoes. This study highlights the increasing frequency of the P. malariae parasite mostly common in asymptomatic individuals with apparent P. falciparum infection. Interventions directed at reducing malaria transmission such as the scaling-up of SP are favoring the emergence and spread of multiple drug-resistant alleles between the human and mosquito host systems.

Plasmodium falciparum drug resistance-associated mutations in isolates from children living in endemic areas of Burkina Faso.

BACKGROUND: Artemisinin-based combinations therapy (ACT) is the current frontline curative therapy for uncomplicated malaria in Burkina Faso. Sulfadoxine-pyrimethamine (SP) is used for the preventive treatment of pregnant women (IPTp), while SP plus amodiaquine (SP-AQ) is recommended for children under five in seasonal malaria chemoprevention (SMC). This study aimed to assess the proportions of mutations in the P. falciparum multidrug-resistance 1 (Pfmdr1), P. falciparum chloroquine resistance transporter (Pfcrt), P. falciparum dihydrofolate reductase (pfdhfr), and P. falciparum dihydropteroate synthase (pfdhps), genes from isolates collected during household surveys in Burkina Faso. METHODS: Dried blood spots from Plasmodium falciparum-positive cases at three sites (Orodara, Gaoua, and Banfora) collected during the peak of transmission were analysed for mutations in Pfcrt (codons 72-76, 93, 97, 145, 218, 343, 350 and 353), Pfmdr-1 (codons 86, 184, 1034, 1042 and 1246) dhfr (codons 51, 59, 108, 164) and dhps (at codons 431, 436, 437, 540, 581, 613) genes using deep sequencing of multiplexed Polymerase chaine reaction (PCR) amplicons. RESULTS: Of the 377 samples analysed, 346 (91.7%), 369 (97.9%), 368 (97.6%), and 374 (99.2%) were successfully sequenced for Pfcrt, Pfmdr-1, dhfr, and dhps, respectively. Most of the samples had a Pfcrt wild-type allele (89.3%). The 76T mutation was below 10%. The most frequent Pfmdr-1 mutation was detected at codon 184 (Y > F, 30.9%). The single mutant genotype (NFSND) predominated (66.7%), followed by the wild-type genotype (NYSND, 30.4%). The highest dhfr mutations were observed at codon 59R (69.8%), followed by codons 51I (66.6%) and 108 N (14.7%). The double mutant genotype (ACIRSI) predominated (52.4%). For mutation in the dhps gene, the highest frequency was observed at codon 437 K (89.3%), followed by codons 436 A (61.2%), and 613 S (14.4%). The double mutant genotype (IAKKAA) and the single mutant genotype (ISKKAA) were predominant (37.7% and 37.2%, respectively). The most frequent dhfr/dhps haplotypes were the triple mutant ACIRSI/IAKKAA (23%), the wild-type ACNCSI/ISKKAA (19%) and the double mutant ACIRSI/ISKKAA (14%). A septuple mutant ACIRNI/VAKKGA was observed in 2 isolates from Gaoua (0.5%). CONCLUSION: The efficacy of ACT partner drugs and drugs used in IPTp and SMC does not appear to be affected by the low proportion of highly resistant mutants observed in this study. Continued monitoring, including molecular surveillance, is critical for decision-making on effective treatment policy in Burkina Faso.

Women's empowerment and uptake of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy: results from a cross-sectional baseline survey in the Lake endemic region, Kenya.

BACKGROUND: Malaria in pregnancy remains a major public health problem in endemic areas of the sub-Saharan African (SSA) region. However, there is limited understanding of the association between women's empowerment and the uptake of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy (IPTp-SP) in Kenya. This study examines the association between women's empowerment indicators (decision-making power, control of assets, education, and employment status) and the uptake of three or more doses of IPTp-SP in the Lake endemic region of Kenya. METHODS: The analysis utilized a dataset from a cross-sectional baseline survey of 3129 women aged 15-49 years in Kisumu and Migori Counties who had a live birth within the last 2 years preceding the study. Data were collected between June to August 2021. A descriptive analysis was conducted to show the distribution of respondents by key background characteristics, and bivariate and multivariate logistic regression to examine statistically significant associations between women's empowerment measures and the uptake of 3+ doses of IPTp-SP. RESULTS: Among the 3129 women surveyed, 1978 (65.7%) received 3+ doses of IPTp-SP during their most recent pregnancy. Controlling for individual characteristics and the number of ANC visits, the odds of taking 3+ doses of IPTp-SP increased among women who had high decision-making autonomy (AOR = 2.33; CI = 1.81-3.01; P < 0.001); and tertiary level of educational attainment (AOR = 1.51; CI = 1.10-2.06). However, the association between control of assets and uptake of IPTp-SP was positive but not statistically significant. CONCLUSION: Women's decision-making autonomy and educational attainment were positively associated with the uptake of IPTp-SP. As a result, maternal health interventions should focus on less empowered women, specifically those with less decision-making autonomy and no/low formal education, as they are less likely to achieve optimal uptake of IPTp-SP during pregnancy.

Effects of maternal antenatal treatment with two doses of azithromycin added to monthly sulfadoxine-pyrimethamine for the prevention of low birth weight in Burkina Faso: an open-label randomized controlled trial.

BACKGROUND: Exposure during pregnancy to malaria and sexually-transmitted infections is associated with adverse birth outcomes including low birth weight (LBW). This study aimed at assessing if the adjunction of two doses of azithromycin to sulfadoxine-pyrimethamine for the intermittent preventive treatment of malaria in pregnancy can reduce LBW. METHODS: A two parallel-groups, open-label randomized controlled trial involving pregnant women (16 to 35 years of age and 12 to 24 weeks of gestation as confirmed by last menstrual period or fundal height) was conducted in rural Burkina Faso. Women were assigned in a 1:1 ratio either to use azithromycin (1 g daily for 2 days) during the second and third trimesters of pregnancy plus monthly sulfadoxine-pyrimethamine (1500/75 mg) (SPAZ) (intervention) or to continue using a monthly sulfadoxine-pyrimethamine (1500/75 mg) (SP) (control). Primary outcome was a LBW (birth weight measured within 24 h after birth < 2500 g). Secondary outcomes including stillbirth, preterm birth or miscarriage are reported together with safety data. RESULTS: A total of 992 pregnant women underwent randomization (496 per group) and 898 (90.5%) valid birth weights were available (450 in SPAZ and 448 in SP). LBW incidence was 8.7% (39/450) in SPAZ and 9.4% (42/448) in controls (p-value = 0.79). Compared with controls, pregnant women with SPAZ showed a risk ratio (RR) of 1.16 (95% confidence interval (CI 0.64-2.08]) for preterm births, 0.75 (95% CI 0.17-3.35) for miscarriage and 0.64 (95% CI 0.25-1.64) for stillbirths. No treatment-related serious adverse events (SAEs) have been observed, and there was no significant difference in the number of SAEs (13.5% [67/496] in SPAZ, 16.7% [83/496] in SP, p-value = 0.18) or AEs (17.1% [85/496] in SPAZ, 18.8% [93/496] in SP, p-value = 0.56). CONCLUSION: Adequate prevention regimen with monthly sulfadoxine-pyrimethamine given to all pregnant women has been proved to reduce the risk of LBW in malaria endemic areas. Adding azithromycin to the regimen does not offer further benefits, as far as women receive a malaria prevention regimen early enough during pregnancy. Trial registration Pan African Clinical Trial Registry ( https://pactr.samrc.ac.za/Search.aspx ): PACTR201808177464681. Registered 21 August 2018.

Seasonal malaria chemoprevention in a context of high presumed sulfadoxine-pyrimethamine resistance: malaria morbidity and molecular drug resistance profiles in South Sudan.

BACKGROUND: Seasonal malaria chemoprevention (SMC) using sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ), is a community-based malaria preventive strategy commonly used in the Sahel region of sub-Saharan Africa. However, to date it has not been implemented in East Africa due to high SP resistance levels. This paper is a report on the implementation of SMC outside of the Sahel in an environment with a high level of presumed SP-resistance: five cycles of SMC using SPAQ were administered to children 3-59 months during a period of high malaria transmission (July-December 2019) in 21 villages in South Sudan. METHODS: A population-based SMC coverage survey was combined with a longitudinal time series analysis of health facility and community health data measured after each SMC cycle. SMC campaign effectiveness was assessed by Poisson model. SPAQ molecular resistance markers were additionally analysed from dried blood spots from malaria confirmed patients. RESULTS: Incidence of uncomplicated malaria was reduced from 6.6 per 100 to an average of 3.2 per 100 after SMC administration (mean reduction: 53%) and incidence of severe malaria showed a reduction from 21 per 10,000 before SMC campaign to a mean of 3.3 per 10,000 after each cycle (mean reduction: 84%) in the target group when compared to before the SMC campaign. The most prevalent molecular haplotype associated with SP resistance was the IRNGE haplotype (quintuple mutant, with 51I/59R/108N mutation in pfdhfr + 437G/540E in pfdhps). In contrast, there was a low frequency of AQ resistance markers and haplotypes resistant to both drugs combined (< 2%). CONCLUSIONS: The SMC campaign was effective and could be used as an additional preventive tool in seasonal malaria settings outside of the Sahel, especially in areas where access to health care is unstable. Malaria case load reduction was observed despite the high level of resistance to SP.

Effects of sulphadoxine-pyrimethamine on maternal, neonatal and placental malaria in Port Harcourt, Rivers State, Nigeria.

BACKGROUND & OBJECTIVES: The utilization of Intermittent Preventive Treatment (sulphadoxine-pyrimethamine) in pregnancy (IPTp-SP) for combating malaria has indicated control over adverse birth outcomes and has been recommended for use by pregnant women. The aim of this study was to determine the effectiveness of IPTp-SP on maternal, neonatal and placental malaria in Port Harcourt, Nigeria. METHODS: 316 samples of maternal peripheral blood (MPB), placental blood (PLB), neonatal cord blood (NCB) and placental tissue (PT) were collected each from consenting mothers. Blood samples were processed and stained by the Giemsa method. Placental tissues were processed and stained in haematoxylin. Examination of samples for malaria parasitaemia was carried out using standard parasitological methods. Demography of participants was collected through questionnaires and from ante natal care (ANC) records. RESULTS: Overall prevalence of 74 (23.42%) was recorded. Age-related prevalence indicated that ≤ 20 years, 9 (56.25%) had the highest prevalence followed by 21-30 years (23.48%), and ≥41 years (16.67%) (p <0.05). Malaria in MPB showed that SP-users had 26 (13.20%) while non-users had 48 (40.33%) (p <0.05). In NCB, SP-users recorded 20 (10.15%) while non-users had 13 (10.92) (p>0.05). The prevalence in PLB and PT revealed that SP-users had a lower prevalence in PLB, 31 (15.73%) and PT, 12 (6.09%) while non-users recorded a higher prevalence 48 (40.33%) in PLB and 21 (17.65%) in PT (P<0.05). INTERPRETATION & CONCLUSION: The utilization of IPTp-SP is seen to significantly reduce the occurrence of malaria in pregnancy, placental tissue and in neonates thereby helping in improving birth outcomes.

Missed opportunities for Intermittent Preventive Treatment of Malaria among pregnant women with the recommended number of antenatal care visits in Nigeria: Secondary Analysis of Malaria Indicator Survey 2021.

BACKGROUND AND OBJECTIVES: Missed opportunity (MO) for IPTp SP remains high in Nigeria even among pregnant women with four or more ANC visits. We assessed the current MO rate and its predictors, using data from the 2021 MIS. METHODS: We carried out a secondary analysis of data of women who had at least one live birth and at least 4 ANC visits. Bivariate analyses assessed the relationship between socio-demographic characteristics, type of ANC facility, type of ANC provider, knowledge of malaria prevention, awareness about IPT, and missed opportunity using the Chi-square test. Multivariate analyses were presented as odd ratios at 95% CI, (P value <0.05). RESULTS: Nearly half (47%) had only primary education or none at all. About 30% were poor. Most had their 1st visit ANC in the 2nd trimester (58%). The missed opportunity rate was 55%. Predictors included age 20 to 34 years [aOR 1.3(1.1-1.67)], being very poor [aOR 1.6(1.1-2.4)], late ANC (in 2nd or 3rd trimester) [aOR 0.57(0.4-0.89)], ignorance about malaria prevention [aOR 1.8(1.4-2.4)], ignorance about IPT [aOR 1.3(1.3-2.5)] and residence in the South South and North East [aOR 0.46(0.31-0.68)] regions. CONCLUSIONS: The missed opportunity was high. Place of residence, poor knowledge of malaria prevention and IPT use, late commencement of ANC, poverty, and young age (20 to 34 years) contributed to the burden. Recommendations include stressing the importance of IPT during health talks. Provision of cups and drinking water for the IPT DOT policy by the Government and partners. There is a need for further research to unravel the reasons for the higher MO rates in some regions.

CONTEXTE: Les opportunités manquées (OM) pour le TPIp SP restent élevées au Nigéria, même parmi les femmes enceintes ayant effectué quatre visites ou plus aux soins prénatals. Nous avons évalué le taux actuel d'OM et ses prédicteurs en utilisant les données de l'Enquête sur les Indicateurs du Paludisme de 2021. MÉTHODE: Nous avons réalisé une analyse secondaire des données des femmes ayant eu au moins une naissance en vie et au moins quatre visites de soins prénatals. Les analyses bivariées ont évalué la relation entre les caractéristiques sociodémographiques, le type d'installation de soins prénatals, le type de prestataire de soins prénatals, la connaissance de la prévention du paludisme, la sensibilisation à propos du TPIp, et les opportunités manquées en utilisant le test du chi-carré. Les analyses multivariées ont été présentées sous forme de cotes ajustées avec un intervalle de confiance de 95 % (valeur de p<0,05). RÉSULTATS: Près de la moitié (47 %) avaient seulement une éducation primaire ou n'en avaient pas du tout. Environ 30 % étaient pauvres. La plupart ont effectué leur 1ère visite prénatale au cours du 2ème trimestre (58 %). Le taux d'opportunités manquées était de 55 %. Les prédicteurs comprenaient l'âge de 20 à 34 ans [aOR 1,3 (1,1-1,67)], être très pauvre [aOR 1,6 (1,1-2,4)], début tardif des soins prénatals (au 2ème ou 3ème trimestre) [aOR 0,57 (0,4-0,89)], ignorance de la prévention du paludisme [aOR 1,8 (1,4-2,4)], ignorance du TPIp [aOR 1,3 (1,3-2,5)] et résider dans les régions du Sud-Sud et du Nord-Est [aOR 0,46 (0,31-0,68)]. CONCLUSION: Les opportunités manquées étaient élevées. Le lieu de résidence, la méconnaissance de la prévention du paludisme et de l'utilisation du TPIp, le début tardif des soins prénatals, la pauvreté et l'âge jeune (20 à 34 ans) ont contribué à cette charge. Les recommandations incluent de souligner l'importance du TPIp lors des entretiens de santé. La fourniture de gobelets et d'eau potable pour la politique de l'administration directe du TPI par le gouvernement et les partenaires. Il est nécessaire de poursuivre la recherche pour découvrir les raisons des taux plus élevés d'OM dans certaines régions. Mots-clés: Paludisme pendant la grossesse, traitement préventif intermittent, sulfadoxine-pyriméthamine, opportunité manquée, soins prénatals.

The Effect of Intermittent Preventive Treatment of Malaria During Pregnancy and Placental Malaria on Infant Risk of Malaria.

BACKGROUND: Intermittent preventive treatment of malaria during pregnancy (IPTp) with dihydroartemisinin-piperaquine (DP) provides greater protection from placental malaria than sulfadoxine-pyrimethamine (SP). Some studies suggest placental malaria alters risk of malaria infection in infants, but few have quantified the effect of IPTp on infant susceptibility to malaria. METHODS: Infants born to women enrolled in a randomized clinical trial comparing IPTp-SP and IPTp-DP in Malawi were followed from birth to 24 months to assess effect of IPTp and placental malaria on time to first malaria episode and Plasmodium falciparum incidence. RESULTS: In total, 192 infants born to mothers randomized to IPTp-SP and 195 randomized to IPTp-DP were enrolled. Infants in IPTp exposure groups did not differ significantly regarding incidence of clinical malaria (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], .58-1.86) or incidence of infection (IRR, 1.18; 95% CI, .92-1.55). Placental malaria exposure was not associated with incidence of clinical malaria (IRR, 1.03; 95% CI, .66-1.59) or infection (IRR, 1.15; 95% CI, .88-1.50). Infant sex, season of birth, and maternal gravidity did not confound results. CONCLUSIONS: We did not find evidence that IPTp regimen or placental malaria exposure influenced risk of malaria during infancy in this population. Clinical Trials Registration. NCT03009526.

An exploratory study of seasonal malaria chemoprevention and pharmacovigilance for under-five children in Kebbi State, Nigeria.

Background: Seasonal malaria chemoprevention (SMC) is an important public health intervention that is being used to reduce the burden of malaria in sub-Saharan Africa. Objectives: This study aimed to evaluate the implementation of SMC and pharmacovigilance practices in under-five children in Kebbi State, Nigeria. Materials and Methods: The methodology involved a comprehensive review of tools for managing SMC commodities, training data collectors, and fieldwork to evaluate all local government area (LGA) stores, the central medical store (CMS), and selected health facilities based on the sample size determined. Data were collected using SurveyCTO software and analyzed using MS Excel. Twenty-one data reviewers visited the CMS, 21 LGA stores, and 315 health facilities. Results: Our study uncovered significant inaccuracies in documentation, which led to many commodities needing to be more effectively accounted for regarding sources. Data triangulation showed inconsistencies between tools and physical counts that do not match the quantities on inventory control cards. Most primary health-care (PHC) staff in charge of SMC have been formally trained in pharmacovigilance. About 75% (237) of PHCs referred cases of adverse drug reactions (ADRs) to a secondary health-care facility, while 14% (45) treated the symptoms of the ADR with another drug, and 7% (21) took no action, and the reaction resolved on its own. Conclusions: This study provides insight into the challenges and opportunities for improving the implementation of SMC and pharmacovigilance practices in Kebbi State, Nigeria, and has important implications for other settings with similar challenges.

The multifaceted antineoplastic role of pyrimethamine against human malignancies.

Cancer accounted for nearly 10 million deaths in 2020 and is the second leading cause of death worldwide. The chemotherapeutic agents that are in clinical practice possess a broad range of severe adverse effects towards vital organs which emphasizes the importance of the discovery of new therapeutic agents or repurposing of existing drugs for the treatment of human cancers. Pyrimethamine is an antiparasitic drug used for the treatment of malaria and toxoplasmosis with a well-documented excellent safety profile. In the last 5 years, numerous efforts have been made to explore the anticancer potential of pyrimethamine in in vitro and in vivo preclinical models and to repurpose it as an anticancer agent. The studies have demonstrated that pyrimethamine inhibits oncogenic proteins such as STAT3, NF-κB, DX2, MAPK, DHFR, thymidine phosphorylase, telomerase, and many more in a different types of cancer models. Moreover, pyrimethamine has been reported to work in synergy with other anticancer agents, such as temozolomide, to induce apoptosis of tumor cells. Recently, the results of phase-1/2 clinical trials demonstrated that pyrimethamine administration reduces the expression of STAT3 signature genes in tumor tissues of chronic lymphocytic leukemia patients with a good therapeutic response. In the present article, we have reviewed most of the published articles related to the antitumor effects of pyrimethamine in malignancies of breast, liver, lung, skin, ovary, prostate, pituitary, and leukemia in in vitro and in vivo settings. We have also discussed the pharmacokinetic profile and results of clinical trials obtained after pyrimethamine treatment. From these studies, we believe that pyrimethamine has the potential to be repurposed as an anticancer drug.

Molecular surveillance of anti-malarial drug resistance genes in Plasmodium falciparum isolates in Odisha, India.

BACKGROUND: Despite significant progress in eliminating malaria from the state of Odisha, India, the disease is still considered endemic. Artesunate plus sulfadoxine-pyrimethamine (AS + SP) has been introduced since 2010 as first-line treatment for uncomplicated Plasmodium falciparum malaria. This study aimed to investigate the prevalence of mutations associated with resistance to chloroquine (CQ), sulfadoxine-pyrimethamine (SP), and artesunate (ART) in P. falciparum parasites circulating in the state. METHODS: A total of 239 isolates of P. falciparum mono infection were collected during July 2018-November 2020 from the four different geographical regions of the state. Genomic DNA was extracted from 200 µL of venous blood and amplified using nested polymerase chain reaction. Mutations on gene associated with CQ (Pfcrt and Pfmdr1) were assessed by PCR amplification and restriction fragment length polymorphism, artemisinin (Pfk13) gene by DNA sequencing and SP (Pfdhfr and Pfdhps) genes by allele-specific polymerase chain reaction (AsPCR). RESULTS: The point mutation in Pfcrt (K76T) was detected 2.1%, in Pfmdr1 (N86Y) 3.4%, and no mutations were found in Pfkelch13 propeller domain. Prevalence of Pfdhfr, Pfdhps and Pfhdfr-Pfdhps (two locus) gene mutations were 50.43%, 47.05% and 49.79% respectively. The single, double, triple and quadruple point mutations in Pfdhfr gene was 11.2%, 8.2%, 17.2% and 3.4% while, in Pfdhps gene was 10.9%,19.5%, 9.5% and 2.7% respectively. Of the total 13 haplotypes found in Pfdhfr, 8 were detected for the first time in the state and of the total 26 haplotypes found in Pfdhps, 7 were detected for the fisrt time in the state. The linked quintuple mutation Pfdhfr (N51I-C59R-S108N)-Pfdhps (A437G-K540E) responsible for clinical failure (RIII level of resistance) of SP resistance and A16V-S108T mutation in Pfdhfr responsible for cycloguanil was absent. CONCLUSION: The study has demonstrated a low prevalence of CQ resistance alleles in the study area. Despite the absence of the Pfkelch13 mutations, high prevalence of Pfdhfr and Pfdhps point mutations undermine the efficacy of SP partner drug, thereby threatening the P. falciparum malaria treatment policy. Therefore, continuous molecular and in vivo monitoring of ACT efficacy is warranted in Odisha.

A qualitative assessment of the health systems factors influencing the prevention of malaria in pregnancy using intermittent preventive treatment and insecticide-treated nets in Ghana.

BACKGROUND: Ghana has adopted and implemented intermittent preventive treatment using sulfadoxine-pyrimethamine (IPTp-SP) and insecticide-treated nets (ITNs) in an antenatal care (ANC) context to prevent malaria among pregnant women. However, the increased ANC attendance and its frequency facilitated by a free maternal health care policy in Ghana does not correspond with the uptake of IPTp-SP and ITN use among pregnant women. This study sought to elucidate the contextual health system factors influencing the delivery of IPTp-SP and ITN from a related quantitative study conducted in Ghana. METHODS: This is the qualitative section of a mixed-methods study design, where audio recorded key informant interviews (KIIs) were conducted with health workers from across health facilities, districts, regional and national health directorates. The KIIs elicited information on health worker knowledge, perceptions, and rationale for the delivery practices of IPTp-SP and ITN revealed in the quantitative findings. The interviews were transcribed and imported into NVivo for analysis. Using the World Health Organization (WHO) Health Systems Framework as the theoretical basis, thematic analysis was conducted under broad themes of the building blocks. Findings are presented in narrative quotes, with a mindmap used to summarize the various health system factors and their interrelated relationship influencing the delivery of IPTp-SP and ITN. RESULTS: Health system factors identified included health staff untrained on malaria delivery directives due to an ineffective trainer of trainer (ToT) system. Additionally, health worker confusion on when to commence SP (at quickening or ≥ 16 weeks) was found to result in delayed start of SP. Stock-outs in facilities due to procurement delays at the national level resulted in missed opportunities to deliver SP to eligible pregnant women at the ANC. Similarly, ITN stock outs led to eligible pregnant women not receiving one at ANC clinics. CONCLUSION: Poor health worker knowledge on policy directives, a consequence of ineffective training strategy led to delayed delivery of IPTp-SP to eligible pregnant women. Supply chain management challenges related to stock of SP and ITN resulted in missed opportunities to deliver the interventions to pregnant women attending ANC.

A cluster randomized trial of delivery of intermittent preventive treatment of malaria in pregnancy at the community level in Malawi.

BACKGROUND: Malaria in pregnancy doubles the risk of low birthweight; up to 11% of all neonatal deaths in sub-Saharan Africa are associated with malaria in pregnancy. To prevent these and other adverse health consequences, the World Health Organization recommends administering intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for all pregnant women at each antenatal care (ANC) visit, starting as early as possible in the second trimester. The target is for countries to administer a minimum of three doses (IPTp3+) to at least 85% of pregnant women. METHODS: A cluster randomized, controlled trial was conducted to assess the effect of delivery of IPTp by community health workers on the coverage of IPTp3 + and ANC visits in Malawi. Community delivery of IPTp was implemented within two districts in Malawi over a 21-month period, from November 2018 to July 2020. In control sites, IPTp was delivered at health facilities. Representative samples of women who delivered in the prior 12 months were surveyed at baseline (n = 370, December 2017) and endline (n = 687, August 2020). A difference in differences analysis was conducted to assess the change in coverage of IPTp and ANC over time, accounting for clustering at the health facility level. RESULTS: Overall IPTp coverage increased over the study period. At baseline, women received a mean of 2.3 IPTp doses (range 0-5 doses) across both arms, and at endline, women received a mean of 2.8 doses (range 0-9 doses). Despite overall increases, the change in IPTp3 + coverage was not significantly different between intervention and control groups (6.9%, 95% CI: -5.9%, 19.6%). ANC4 + coverage increased significantly in the intervention group compared with the control group, with a difference-in-differences of 25.3% points (95% CI: 1.3%, 49.3%). CONCLUSIONS: In order to reduce the burden of malaria in pregnancy, new strategies are needed to improve uptake of effective interventions such as IPTp. While community health workers' delivery of IPTp did not increase uptake in this study, they may be effective in other settings or circumstances. Further research can help identify the health systems characteristics that are conducive to community delivery of IPTp and the operational requirements for effective implementation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03376217. Registered December 6, 2017, https://clinicaltrials.gov/ct2/show/NCT03376217 .